Recombination between related, repeat elements within the genome may lead to alterations in adjacent sequences or translocations, both potentially damaging to normal metabolism. We are investigating mechanisms and genetic control of recombination between diverged DNAs in bacteria and the model eukaryote, the yeast Saccharomyces cerevisiae. With E. coli we are addressing questions of how mismatch repair systems prevent recombination--is it prior to or following the formation of hybrid DNAs. Hybrid molecules are prepared in vitro between DNAs that are diverged and transformed into wild type and various mismatch deficient mutants. The likelihood of survival of the molecules depends both on their configuration and the host. Since transforming molecules that have recombinant intermediate configurations exhibit high survival in mismatch proficient hosts, we propose that mismatch repair influences recombination mostly at the time hybrid molecules are being formed. Using yeast we have examined the role of DNA organization and replication in recombination between highly diverged (28%) molecules. Altered replication in a POLIII replicative polymerase mutant greatly enhances recombination. An even greater effect is found when the direct, but diverged, repeats are separated by a long inverted repeat. These results demonstrate that the capability for aberrant recombination can be influenced over 1000 fold by a combination of altered replication and chromosome organization. Our observations follow up on those of the previous year where we suggested a novel mechanism for the involvement of replication in double-strand break induced recombination between diverged DNAs.